Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor&ndash;ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer.

fig2: Interactions of immune checkpoint receptors and ligands affecting NK cell functions. NK cells (bottom) express multiple immune checkpoint receptors and ligands. The green color represents receptors and the blue color represents ligands. The ligands on tumor cells are well known to interact with their cognate receptors on NK cells, but it has been reported that ligands on NK cells also interact with their receptors on dendritic cells (DCs) or Tregs; for example, PD-1 on DCs and CTLA-4 on Tregs. However, the effects of the interactions on anti-tumor activity of NK cells may require further confirmation. The dotted lines indicate that the interactions may require further investigation, whereas the interactions marked with solid lines are less debatable. The names in the boxes (middle) show blocking agents that are currently available in clinic.

Mentions:
Recent progress in the blockade of immune checkpoints have mostly focused on Programmed cell death protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Figure 2). There are three FDA-approved drugs to inhibit PD-1 or CTLA-4 pathways.97 Ipilimumab is a human IgG1 antibody (Ab) used for CTLA-4 blockade. Nivolumab is a human IgG4 Ab specific for PD-1. Both were developed by Bristol–Myers Squibb. Pembrolizumab by Merck (Kenilworth, NJ, USA) is a humanized IgG4 Ab directed against PD-1. More immune checkpoint inhibitors are currently in clinical trials. PD-1 is highly expressed on approximately one-fourth of peripheral blood NK cells in healthy humans. It is expressed by CD56dimNKG2A−KIR+CD57+ mature NK cells, but not by CD56bright NK cells.98 PD-1+ NK cells are likely resting NK cells.99 PD-1 is upregulated on NK cells from Kaposi sarcoma patients, mediating impaired NK cell function.100 Treatment with an anti-PD-1 Ab enhances human NK cell cytotoxicity against autologous multiple myeloma cells in vitro.101 CTLA-4 itself is expressed by activated mouse NK cells and inhibits cytokine production in response to mature dendritic cells.102 The expression of the CTLA-4 and CD28 ligands CD80 and CD86 on cancer cells enhance the cytotoxicity of human NK cells.103 CTLA-4+ Tregs suppress NK cell cytotoxicity in Cetuximab (anti-EGFR Ab)-treated head and neck cancer patients.104 However, it has been proposed that B7.1-CD28/CTLA-4 is not involved in triggering human NK cell activation in a previous study.105 Furthermore, CD28/B7 co-stimulation does not appear to play an important role in peripheral NK cells in murine cytomegalovirus infection.106 Taken together, it remains unclear whether anti-CTLA-4 therapy could improve the anti-cancer effect of NK cells.

fig2: Interactions of immune checkpoint receptors and ligands affecting NK cell functions. NK cells (bottom) express multiple immune checkpoint receptors and ligands. The green color represents receptors and the blue color represents ligands. The ligands on tumor cells are well known to interact with their cognate receptors on NK cells, but it has been reported that ligands on NK cells also interact with their receptors on dendritic cells (DCs) or Tregs; for example, PD-1 on DCs and CTLA-4 on Tregs. However, the effects of the interactions on anti-tumor activity of NK cells may require further confirmation. The dotted lines indicate that the interactions may require further investigation, whereas the interactions marked with solid lines are less debatable. The names in the boxes (middle) show blocking agents that are currently available in clinic.

Mentions:
Recent progress in the blockade of immune checkpoints have mostly focused on Programmed cell death protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (Figure 2). There are three FDA-approved drugs to inhibit PD-1 or CTLA-4 pathways.97 Ipilimumab is a human IgG1 antibody (Ab) used for CTLA-4 blockade. Nivolumab is a human IgG4 Ab specific for PD-1. Both were developed by Bristol–Myers Squibb. Pembrolizumab by Merck (Kenilworth, NJ, USA) is a humanized IgG4 Ab directed against PD-1. More immune checkpoint inhibitors are currently in clinical trials. PD-1 is highly expressed on approximately one-fourth of peripheral blood NK cells in healthy humans. It is expressed by CD56dimNKG2A−KIR+CD57+ mature NK cells, but not by CD56bright NK cells.98 PD-1+ NK cells are likely resting NK cells.99 PD-1 is upregulated on NK cells from Kaposi sarcoma patients, mediating impaired NK cell function.100 Treatment with an anti-PD-1 Ab enhances human NK cell cytotoxicity against autologous multiple myeloma cells in vitro.101 CTLA-4 itself is expressed by activated mouse NK cells and inhibits cytokine production in response to mature dendritic cells.102 The expression of the CTLA-4 and CD28 ligands CD80 and CD86 on cancer cells enhance the cytotoxicity of human NK cells.103 CTLA-4+ Tregs suppress NK cell cytotoxicity in Cetuximab (anti-EGFR Ab)-treated head and neck cancer patients.104 However, it has been proposed that B7.1-CD28/CTLA-4 is not involved in triggering human NK cell activation in a previous study.105 Furthermore, CD28/B7 co-stimulation does not appear to play an important role in peripheral NK cells in murine cytomegalovirus infection.106 Taken together, it remains unclear whether anti-CTLA-4 therapy could improve the anti-cancer effect of NK cells.

Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor&ndash;ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer.